My initial project described an effector B cell population that protects against microbial sepsis. In the published work I characterized the new Innate response activator (IRA)-B cells. IRA-B cells are phenotypically and functionally distinct, develop and diverge from B1a B cells, depend on pattern recognition receptors, and produce GM-CSF. Specific deletion of IRA-B cell activity impaired bacterial clearance, elicited a cytokine storm, and precipitated septic shock. These observations enrich our understanding of innate immunity, position IRA-B cells as gatekeepers of bacterial infection, and identify new treatment avenues for infectious diseases. In a second project I characterized the role of IRA B cells in pneumonia. Pneumonia is a major cause of mortality worldwide and a serious problem in critical care medicine, but the immunophysiological processes that confer protection or morbidity are incompletely understood. Ongoing studies show that in response to lung infection, B1a B cells migrate from the pleural space to the lung parenchyma to secrete emergency immunoglobulin-M (IgM). The process requires innate response activator (IRA) B cells, a transitional, B1aderived inflammatory subset that controls IgM production via autocrine granulocytemacrophage colony stimulating factor (GM-CSF) signaling. The strategic location, coupled with the capacity to produce GM-CSF-dependent IgM, ensures effective early frontline defense against bacteria invading the lungs. The study describes a previously unrecognized GM-CSF-IgM axis and positions IRA B cells as orchestrators of protective IgM immunity. In a third project I concentrated my work on the initial phase of sepsis and the role of Interleukin(IL)-3. Sepsis is a frequently fatal condition characterized by an uncontrolled host reaction to microbial infection. Human studies have shown that sepsis is associated with excessive production of inflammatory cytokines – an event known as a cytokine storm. Clinical trials targeting inflammatory mediators have failed, however, creating an urgent need for a better fundamental understanding of sepsis’ pathophysiology. Ongoing studies show that IL-3 is an essential inducer of inflammation in sepsis. Although almost undetectable in the steady state, IL-3 expression was pronounced in response to microbial infection in a mouse model. Within hours, IL-3 amplified hematopoiesis in the bone marrow and spleen, generating monocytosis and neutrophilia. Among the leukocytes, Ly-6Chigh monocytes contributed substantially to the ensuing cytokine storm by producing abundant IL-1β, TNFα, and IL-6. As a consequence, IL-3 precipitated multi-organ damage, septic shock, and death. The cellular source of IL-3 were the innate response activator (IRA) B cells which arose from peritoneal B1 cells via direct recognition of bacteria at the site of infection. Injection of antibodies against the IL-3-specific receptor in mice reduced morbidity and mortality. Altogether, this study enriches our understanding of immune activation, and identifies IL-3 as an orchestrator of emergency hematopoiesis and a potential therapeutic target for the treatment of sepsis.